An ULK1/2-PXN mechanotransduction complex suppresses breast cancer cell migration

Abstract

AbstractThe remodeling and stiffening of the extracellular matrix (ECM) associated with breast cancers is a well-recognized modulator of disease progression. However, how changes in the mechanical properties of the ECM are converted into biochemical signals that direct tumor cell migration and metastasis remains poorly characterized. Here, we describe a new role for the autophagy-inducing serine/threonine kinases ULK1 and ULK2 in mechanotransduction. We demonstrate that ULK1/2 activity inhibits the assembly of actin stress fibers and focal adhesions (FAs), and as a consequence impedes cell contraction and migration. Mechanistically, we identify PXN/paxillin, a key component of the mechanotransducing machinery, as a direct binding partner and substrate of ULK1/2. ULK-mediated phosphorylation of PXN at S32 and S119 weakens homotypic interactions and liquid-liquid phase separation of PXN, impairing FA assembly, which in turn impedes the mechanotransduction of breast cancer cells. ULK1/2 and the well characterized PXN regulator, FAK/Src, have opposing functions on mechanotransduction and compete for phosphorylation of adjacent serine and tyrosine residues. Thus, our study reveals ULK1/2 as important regulators of PXN-dependent mechanotransduction.HighlightsULK1/2 interact with PXN and phosphorylate PXN at S32 and S119 in response to mechanical stimuliULK1/2-mediated phosphorylation of PXN regulates mechanotransduction and migration of breast cancer cellsULK1/2 modulate the biomaterial properties of focal adhesions through PXN phosphorylationULK1/2 and FAK/Src act antagonistically in mechanotransduction through competitive phosphorylation of PXN